Exploring POPDC1 as a Therapeutic Target in Multiple Cancers

This literature review investigates the role of POPDC1, a cAMP-binding protein, as a potential therapeutic target in breast cancer and other cancers. It highlights the molecular biology of POPDC, its interaction with cAMP, and its impact on cancer cell migration and metastasis. The review examines existing research, noting that POPDC1 expression is often suppressed in malignant cancer cells, leading to increased migration and poor clinical outcomes. It also discusses how targeting the Popeye domain of POPDC1, a unique cAMP binding motif, could prevent functional loss and inhibit cancer progression. The review identifies a literature gap in understanding the precise mechanisms of POPDC1 function and suggests future research directions for establishing potential drug targets. This document is available on Desklib, a platform offering study tools and resources for students.

Running head: BREAST CANCER
Name of the student:
Name of the university:
Author note:

1
BREAST CANCER
Introduction:
Molecular heterogeneity of Breast cancer has resulted in the disparities in the therapeutic
responses and targeting molecular subtypes of breast cancer. This disparities further intensifying
the necessity of identification and validation of the novel therapeutic target for breast cancer
target (Kiessling and Ashton 2017). Considering the molecular targeting of breast cancer,
POPDC 1 plays a massive role in metastasis behavior of the cancerous cells. POPDC genes are
found throughout the animal kingdom and are a novel class of c-AMP effector with multiple
functions in multiple tissues (Csutak et al. 2016). POPDC protein is a member of membrane-
tethered protein encoded by three members of family POPDC1, 2 and 3 (Pop and Nagy 2016).
Various single cell migration assay suggested that these cells are expressed in cardiac and
skeletal muscles and may act as cell adhesion molecules (Brand 2018). Brand and Schindler
(2016), suggested that suppression of the gene is correlated with the disease progression and
poor clinical outcome in various cancer such as breast cancer, gastric cancer, lungs cancer
hepatocellular sarcoma and colorectal cancer. There is a mountain of literature which suggested
that Popeye domain of POPDC binds to the secondary messenger c-AMP with a high affinity
which predominantly expressed in heart (Di Benedetto , Gerbino and Lefkimmiatis 2018). The
function of this gene, especially POPDC1 is to involve in the cell to cell contact formation and
regulation of epithelial function (Deming et al. 2018). Moreover, it is an essential gene which
shown to be an essential component of tight junctions for proper epithelial cell function
(Rukoyatkina et al. 2018). Loss of POPDC protein expression has been correlated with
increased cancer migration and invasion, drug resistance and poor patient survival (Inoue, Tani
and Tagaya 2016). This paper will illustrate the scope of the review and ration behind it,
molecular structure POPDC, role of POPDC 1 in breast cancer , the interaction between POPDC

2
BREAST CANCER
and CAMP, in-depth study of POPDC for drug target ,literature gap, the future direction of
research in following paragraphs.
The scope of the review and the rationale behind choosing the topic:
Various single cell migration assay, cell population migration assay highlighted that
although POPDC proteins are drivers of all kinds of cancer cell migration and proliferation, the
expression pattern is highest in the nonmalignant breast cancer cells and lowest in the malignant
bread cancerous cells (Amunjela 2017). This result further suggested that the loss of POPDC
protein expression correlates with an increase in malignant phenotype of cells that further
increase the health care expenditures and morbidity rate (Mustachio et al. 2016). Therefore,
breast cancer has been chosen for conducting a literature review through primary research. Thus
on a concluding note, this paper intended to conisder and predict molecular targeting of the
Popeye domain of POPDC in breast cancer. Apart from, this paper will give the concise idea of
topic related to POPDC as well as literature gap and the future direction of the research as a
crucial contribution in literature for the readers.
Discussion:
Molecular biology of POPDC:
Tumor growth and metastasis are major challenges in cancer treatment and metastasis
which further increased in the primary cause of more than 90% of deaths of cancer patients with
solid tumor patient (Balaban et al. 2017). Therefore, this incidence further draws the attention of
the researchers for identification of clinically relevant anti-cancer which result in the maximum

3
BREAST CANCER
clinical effect with minimal side effects (Peela et al. 2016). Hong et al. (2016), highlighted
that POPDC is an encoded by popdc1, 2 and 3 which is highly expressive in skeletal muscles and
heart muscles and few expression also found in smooth muscle tissue of bladder, the
gastrointestinal tract. The abundance of expression not only limited to these areas but also found
in central and autonomic nervous system, epithelial cells or retina and cornea of eyes. Campbell
et al. (2016), highlighted that these three genes are located in different chromosomal loci and
generally separated by an intragenic sequence and due to overlapping transcription, the
expression of POPDC1 is higher to other two genes (Sharaf et al. 2016). Popeye domain is one
of the unique domains which show the highest level of sequence conservation within POPDC
that further suggested that this protein domain may have further molecular importance. The
affinity of binding with Camp is shared by the POPDC2 and 3 and due to the difference in 20
fold; POPDC1 is preferential binds with the c-AMP. The possible explanation of the affinity also
observed due to the structural similarity between the structural similarities to the cAMP-binding
domain of protein kinase A (PRKAR2B). c-AMP acts as an intracellular massager as well as
further involves in the cell to cell adhesion and interactions (Huang et al. 2016). Upon binding,
POPDC undergoes conformational changes which Furth the cell to cell interaction and regulate
the regulation of the epithelial cell. Therefore, c-AMP regulates the expression of POPDC in
breast cancer.
Role of POPDC 1 in breast cancer:
Breast cancer is the second leading cause of cancer-associated morbidity and mortality
rate worldwide. It classified in luminal A, luminal B, HER2 positive and basal-like according to
the expression of epidermal growth factor receptor 2, estrogen and progesterone expression.
Amunjela and Tucker (2017) conducted a cell proliferation assay, pull-down assay, paired T-

4
BREAST CANCER
tests as well as immunocytochemistry to evaluate the role of POPDC1 in breast cancer. The
researchers worked on the non-malignant breast cell line (MCF10A), a less aggressive luminal a
breast cancer cell line (MCF7) and aggressive breast cancer cell lines MDA231 to evaluate the
role of The POPDC in breast cancer. The result suggested that the absence of the function of the
POPDC1 dimers in the breast cancer cell membranes leads to the rapid reduction in POPDC1
mediated tight junction maintenance in the patient which thereby promotes the cell migration.
The researchers suggested that suppression significantly promotes the migration in MCF7,
MDA231 cells. The authors suggested that binding of cAMP to Popeye domain can induce the
over expression of POPDC and hinders the migration. The detailed research was conducted by
other researchers. The similar kind of research was conducted by the same authors, Amunjela
and Tucker (2016), where they suggested that Popeye domain containing Protein are a novel
class of Camp binding molecules which affects the cancerous behavior and associated with poor
clinical outcome. The authors conducted a systematic review which is a secondary study to
evaluate the role of POPDC in breast cancer and how cAMP effectively bind the POPDC to
prevent loss of function and migration of the cells. However, correlated studies included in the
journal suggests that these proteins are less ubiquitous than other cAMP targets in a body, the
majority of the POP DC proteins were observed in cardiac or skeletal muscles compared to the
other c-AMP targets which are ubiquitous throughout the body (Huang et al. 2016). Therefore,
although the binding of the c-AMP with the POPDC is effective for preventing functional loss, it
is difficult to target them. Besides, the authors also highlighted that c-AMP is not only the target
for POPDC, c-AMP also identified as potential binding sites for POPDC. At physiological
concentration, cGMP is not an efficient target for POPDC rather it binds to cAMP to involve in
the cell to cell contact and regulating epithelial cells. cGMP only Identified as the potential

5
BREAST CANCER
target site for POPDC only it’s physiological concentration is higher to cAMP. Although the
authors conducted the secondary study to evaluate the roles, this review is useful to gain an
understanding of breast cancer progression and research of the associated studies conducted on
the same topic. However, primary studies are required to undertake to investigate the behavior of
cancerous cells and the role of cAMP in the reduction of it. Therefore, loss of POOPDC1
function can be potentially prevented by targeting mutation which hinders protein to loss from
the cell membrane and stabilizes the protein in the cell membrane. The similar kind of research
conducted by Amunjela and Tucker (2017) which was published in another journal where
authors conducted cell proliferation assay, Western blot, EGFR and AG1478 treatment to
evaluate the role of the POPDC1 in breast cancer. The result suggested that POPDC1 suppressed
in human breast cancer tissues and is negatively regulated by EGFR in breast cancer cell lines.
Epidermal growth factor receptor 2 is a member of the tyrosine kinase receptor. EGFR is
overexpressed in many cancerous cells especially in breast cancer and indicate poor prognosis
and clinical outcomes and lastly, associated with advanced disease. Activated EGFR has been
shown to suppress the function of POP DC by impairing the function of POPDC which further
increase the cell migration, proliferation. Therefore, researchers suggested that a relay protein
with a PTB or SH2 domain may interact with phosphotyrosine binding domain of EGFR which
either directly interact with POPDC 1 or induce phosphorylation of POPDC1 which further
leads to loss of function and the migration of cancerous cells. The authors suggest
overexpression of POPDC1 inhibit EGFR mediated transmitted tumorgenesis in breast cancer.
Although, the authors suggested that EGFR binds to POPDC 1 induce loss of function but the
exact mechanism was not described rather it was hypothesized by them to find out the potential

6
BREAST CANCER
drug target. Therefore, further research is required to undertake for established potential drug
target.
The interaction between POPDC and cAMP:
Accumulated evidence not only focused on the role of POPDC in cancer cells but also
focused on the interaction between POPDC and CAMP to identify potential drug target for
preventing the migration of cancerous cells (Balaban et al. 2017). Majority of the study
undertaken in this paper is focused on breast cancer because of the highest suppression of
POPDC whereas the role of POPDC in other than breast cancers are observed. The alternative
studies suggested that the loss of POPDC not only promotes the migration of the cancerous
cells but also promotes the cardiac and skeletal muscle pathologies which can be inhibited by
further reduced by regained function of POPDC1 (Di Benedetto , Gerbino and Lefkimmiatis
2018). Jiang et al. (2017), aimed to investigate the signaling pathway of cAMP in human to find
the effectors and how it is manipulated in the patient with cancers. The authors conducted optical
experiments considering FRET-based sensors designed around an Epac backbone. The result
suggested that cAMP only binds with POPDC and CRIS in higher affinity. Where CRIS
(cyclic nucleotide receptor involved in sperm function) only shown to control the sperm and
flagellar movement in microorganism upon binding with cAMP, POPDC plays the more critical
role in amending the normal functioning of human anatomy. Jiang et al. (2017), highlighted that
POPDC proteins can interact with cAMP and modulate the functions of ion channels which
present in the plasma membrane in A cAMP Dependent fashion. Since it is POPDC is
predominant in cardiac and skeletal muscles, the binding influence the construction of the
cardiac and skeletal muscles. Consequently, loss of function of POPDC not only stimulate the

7
BREAST CANCER
migration but also influence the cardiac and skeletal muscles, as mentioned above which further
have an effect on the normal heart rate of the individuals.
In-depth study of POPDC for drug target:
There are the numbers of primary and secondary research was conduct to identify the role
of POPDC in order to prevent the loss of function which further stimulates the migration of the
cancerous cells (Balaban et al. 2017). The accumulated evidence identified two-pore channel
TREK-1 and Caveolin as a POPDC which mostly suppressed in cancerous patient whereas
Caveolin 3 is identified as a most crucial protein which is suppressed in cancer, especially breast
cancer. Hong et al. (2016), suggested that Caveolin is the principal structural protein of
caveolae, especially caveolin, cholesterol, and sphingolipid-enriched invagination of the plasma
membrane that involved in signal transduction and vesicular trafficking. Di Benedetto, Gerbino
and Lefkimmiatis (2018)study highlighted that while caveolae-dependent signaling occurred in
the body, caveolin 1 acts as a scaffold protein to organize multicellular signaling. However, gene
mapping of caveolin suggested that it has tumor suppression locus to suppress the growth of the
tumor in the body which shows frequent deletion mutation in breast sarcoma that further induces
the migration of cancerous cells .to investigate (Inoue, Tani and Tagaya 2016). To investigate
stromal caveolin-1 and caveolin-2 expression in primary tumors and lymph node metastases,
Gerstenberger et al. (2018) conducted tissue microarrays from patient samples, CAV1, and
CAV2 Immunohistochemistry and Scoring and Statistical Analyses by chi-square test. The result
suggested that CAV1 and CAV2 are down-regulated in the stromal cells in cancer patients,
especially breast cancer and lung cancer. In breast cancer the absence of stromal CV1 is
associated with poor prognosis of the malignancy. Therefore, experiments suggested that
replacing caveolin 1 or targeting its signaling pattern and associated signaling partner can be a

8
BREAST CANCER
novel therapeutic target for breast cancer. Besides, forced endogenous or recombinant re-
expression of caveolin or formulating molecules which mimics the function of caveolin can be
an effective therapeutic target for reducing breast cancer.
Conclusion:
On a concluding note, Tumour growth and metastasis are major challenges in cancer
treatment and metastasis which further increased in the primary cause of death of a significant
number of patient with the solid tumor. To evaluate the behavior of cancerous cells in the body
and identifying the molecular target of cancer, the massive role of POP DC 1 plays in metastasis
behavior of the cancerous cells is required to consider. POPDC encoded by three members of
family POPDC1, 2 and 3 which is predominant in the cardiac and skeletal muscles. However,
breast cancer chosen for this paper since the expression pattern is highest in the non-malignant
breast cancer cells and lowest in the malignant bread cancerous cells. The loss of POPDC
protein expression correlates with an increase in malignant phenotype of cells. The study
highlighted that the loss of POPDC nit only promotes the migration of the cancerous cells but
also promoted the cardiac and skeletal muscle pathologies. POPDC proteins can interact with
CAMP and modulate the functions of ion channels of the plasma membrane that further
influence the contraction of cardiac muscles. Therefore, accumulated evidence showed that
CAMP binding with POPDC prevents the loss of POPDC and further migration of cancerous
cells. Therefore, Induced binding of CAMP can act a novel therapeutic target. The study further
showed that Activated EGFR has been shown to suppress the function of POPDC by impairing
the function of POPDC which further increase the cell migration, proliferation. Therefore,
forced inhibition of EGFR can prevent the loss of POPDC which further can act drug target. The
in-depth study suggested that Caveolin is one of POPDC which has a tumor suppression locus

9
BREAST CANCER
and frequent deletion mutation causes the loss of function. Therefore, forced expression of
Caveoline or administering Caveoline analog can act as a drug target for the prevention of
malignancy.
Literature gap:
Despite having a set of diverse literature which contributed to the research of cancer ,
there are literature gap existed in the literature which further shows the direction of future
research. In the current context, although the Role of POPDC1 in breast cancer and lung was
explored, the detailed study is required to explore the role of POPDC 1 in other cancers for
targeting it as a drug for future. Moreover, the majority of the study conducted considering the
cell lines such as (MCF10A),(MCF7), MDA231. SkBr3 and T-47D were not considered as a
cell line for conducting research. Moreover, considering caveolin 1 as POPDC1 protein, it can
interact with H-ras, TGF beta receptor 1, estrogen receptor alpha, epithelial growth factor
receptor, nitric oxidase 2. However, CAMP and epithelial growth factor receptor interaction
were considered in evaluating the functional loss of the POPDC, no other effector molecules
were considered for preventing the functional loss of POPDC. TGF beta receptor 1 is a
multifunctional cytokine which interacts with POPDC and has an ability to resist the migration
of the cancer cells which was inactivated during migration of cancerous cells. The detailed study
was required to establish an over expression of TGF beta receptor 1 and interaction of with
caveolin 1 as an immune therapy for reducing cancer-associated morbidity and mortality rate.
No study considered the deletion mutation prevention of caveolin 1. Considering epithelial
growth factor receptor, overexpression of it stimulates functional loss of POPDC but the pathway
was not well established, the majority of the researchers hypothesized about the binding domain.
The detailed study is required to establish a drug target of it. besides, the researches were

10
BREAST CANCER
conducted in the cell lines, very few researchers explored actual cancer patient to evaluate the
role. Therefore, the sample from cancer patient required to collect to observe the differences
between the experimental setup and changes observed in environmental set up. This further
gives rise to research selection bias and inaccuracy of the result.
The future direction of research:
Considering the literature gap, a detailed study is required for the Role of POPDC1 for
other cancers to establish it as a potential drug target. Apart from considering the breast cancer
cell lines such as (MCF10A),(MCF7), MDA231, experiments on SkBr3 and T-47D is required
to conduct for gain the understanding the behavior of cancerous cells and role of POPDC1 in the
prevention of malignancy. Researches on Other interactive molecules of caveoline1 are required
for establishing alternative drug target apart from CAMP. The research on The pathway of the
interaction between epithelial growth factor receptor and POP DC 1 is required to prevent the
over-activation of EGFR as the drug target. The researcher required to explore the field of
immunology for constant activation of TGF beta receptor 1 which further prevent malignant cell
metastasis. Lastly, since the majority of the study was conducted in breast cancer cell line, very
few studies were conducted taking the sample from the women with breast cancer, the sample
from women with breast cancer is required to consider for investigating any changes because of
the environment. During this research socio-demographic status of these women is required to
consider to evaluate the impact of variation of the environment on the breast cancer patient.

11
BREAST CANCER
References:
Amunjela, J. N. and Tucker, S. J. 2017. Dysregulation of POPDC1 promotes breast cancer
cell migration and proliferation. Bioscience reports, 37(6), BSR20171039.
Amunjela, J. N.,and Tucker, S. J. 2016. POPDC proteins as potential novel therapeutic
targets in cancer. Drug discovery today, 21(12), 1920-1927.
Amunjela, J.N. and Tucker, S.J., 2017. POPDC1 is suppressed in human breast cancer tissues
and is negatively regulated by EGFR in breast cancer cell lines. Cancer letters, 406, pp.81-
92.
Amunjela, J.N., 2017. The roles of POPDC proteins in the migration and proliferation of
breast cancer cells (Doctoral dissertation, University of Aberdeen). 589, pp.81-92.
Balaban, S., Shearer, R.F., Lee, L.S., van Geldermalsen, M., Schreuder, M., Shtein, H.C.,
Cairns, R., Thomas, K.C., Fazakerley, D.J., Grewal, T. and Holst, J., 2017. Adipocyte
lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast
cancer cell proliferation and migration. Cancer & metabolism, 5(1), p.1.
Bhatia, M., McGrath, K.L., Di Trapani, G., Charoentong, P., Shah, F., King, M.M., Clarke,
F.M. and Tonissen, K.F., 2016. The thioredoxin system in breast cancer cell invasion and
migration. Redox biology, 8, pp.68-78.
Brand, T. and Schindler, R.F., 2016. The Popeye domain containing protein family-a novel
class of cAMP effectors with important functions in multiple tissues.

12
BREAST CANCER
Brand, T., 2018. The popeye domain containing genes and their function as cAMP effector
proteins in striated muscle. Journal of cardiovascular development and disease, 5(1), p.18.
Campbell, J.J., Husmann, A., Hume, R.D., Watson, C.J. and Cameron, R.E., 2017.
Development of three-dimensional collagen scaffolds with controlled architecture for cell
migration studies using breast cancer cell lines. Biomaterials, 114, pp.34-43.
Csutak, C., Ordeanu, C., Nagy, V.M., Pop, D.C., Bolboaca, S.D., Badea, R., Chiorean, L. and
Dudea, S.M., 2016. A prospective study of the value of pre-and post-treatment magnetic
resonance imaging examinations for advanced cervical cancer. Clujul Medical, 89(3), p.410.
Deming, P.B., Campbell, S.L., Stone, J.B., Rivard, R.L., Mercier, A.L. and Howe, A.K.,
2015. Anchoring of protein kinase A by ERM (ezrin-radixin-moesin) proteins is required for
proper netrin signaling through DCC (deleted in colorectal cancer). Journal of Biological
Chemistry, 290(9), pp.5783-5796.
Di Benedetto, G., Gerbino, A. and Lefkimmiatis, K., 2018. Shaping mitochondrial dynamics:
The role of cAMP signalling. Biochemical and biophysical research
communications, 500(1), pp.65-74.
Gerstenberger, W., Wrage, M., Kettunen, E., Pantel, K., Anttila, S., Steurer, S. and Wikman,
H., 2018. Stromal Caveolin-1 and Caveolin-2 Expression in Primary Tumors and Lymph
Node Metastases. Analytical Cellular Pathology, 2018
Hong, Y., Liang, H., Wang, Y., Zhang, W., Zhou, Y., Yu, M., Cui, S., Liu, M., Wang, N.,
Ye, C. and Zhao, C., 2016. miR-96 promotes cell proliferation, migration and invasion by
targeting PTPN9 in breast cancer. Scientific reports, 6, p.37421.

13
BREAST CANCER
Huang, F., Shi, Q., Li, Y., Xu, L., Xu, C., Chen, F., Wang, H., Liao, H., Chang, Z., Liu, F.
and Zhang, X.H.F., 2018. HER2/EGFR–AKT Signaling Switches TGFβ from Inhibiting Cell
Proliferation to Promoting Cell Migration in Breast Cancer. Cancer research, 78(21),
pp.6073-6085.
Inoue, H., Tani, K. and Tagaya, M., 2016. SNARE-associated proteins and receptor
trafficking. Receptors & Clinical Investigation, 3(3).
Jiang, J. Y., Falcone, J. L., Curci, S., and Hofer, A. M. 2017. Interrogating cyclic AMP
signaling using optical approaches. Cell calcium, 64, 47-56.
Kiessling, C.J. and Ashton, K., 2017. A Deeper Look into the Cellular Caves: Caveolins,
Cavins and Popdc Proteins in Cardioprotection. THE BANGKOK MEDICAL
JOURNAL, 13(1).
Mustachio, L.M., Lu, Y., Tafe, L.J., Andrew, A.S., Memoli, V., Rodriguez-Canales, J.,
Villalobos, P.A., Wistuba, I., Yu, J., Lee, J.J. and Chinyengetere, F., 2016. Loss of the
ubiquitin protease USP18 represses KRAS mutant lung cancer tumorigenicity in mice by
destabilizing KRAS protein.
Peela, N., Sam, F.S., Christenson, W., Truong, D., Watson, A.W., Mouneimne, G., Ros, R.
and Nikkhah, M., 2016. A three dimensional micropatterned tumor model for breast cancer
cell migration studies. Biomaterials, 81, pp.72-83.
Pop, D.C. and Nagy, V.M., 2016. Intracavitary Brachytherapy in Cervical Cancer: a Physics
Perspective. Journal of Radiotheraphy & Medical Oncology, 22(1), pp.10-16.

14
BREAST CANCER
Rukoyatkina, N., Butt, E., Subramanian, H., Nikolaev, V.O., Mindukshev, I., Walter, U.,
Gambaryan, S. and Benz, P.M., 2017. Protein kinase A activation by the anti-cancer drugs
ABT-737 and thymoquinone is caspase-3-dependent and correlates with platelet inhibition
and apoptosis. Cell death & disease, 8(6), p.e2898.
Schindler, R.F., Poon, K.L., Simrick, S. and Brand, T., 2012. The Popeye domain containing
genes: essential elements in heart rate control. Cardiovascular diagnosis and therapy, 2(4),
p.308.
Sharaf, H., Matou-Nasri, S., Wang, Q., Rabhan, Z., Al-Eidi, H., Al Abdulrahman, A. and
Ahmed, N., 2015. Advanced glycation endproducts increase proliferation, migration and
invasion of the breast cancer cell line MDA-MB-231. Biochimica et Biophysica Acta (BBA)-
Molecular Basis of Disease, 1852(3), pp.429-441.
Wehbi, V.L. and Taskén, K., 2016. Molecular mechanisms for cAMP-mediated
immunoregulation in T cells–role of anchored protein kinase A signaling units. Frontiers in
immunology, 7, p.222.